The present invention relates to (2S)-enantiomers of 2-aminoindan derivatives and a novel process for the preparation of them.
Schizophrenia is a common and devastating mental disorder which is currently an unmet medical need. It is characterized by so-called positive (hallucinations, delusions) and negative (blunted affect, poverty of speech, social and emotional withdrawal) symptoms, as well as cognitive deficits (working memory impairment). About 1% of the world population is affected, men and women equally, with typical onset between ages 15 and 25. Antagonists of the neurotransmitter dopamine are known to block psychosis. The present invention provides compounds of formula I (wherein each R is independently C1-8 alkyl), a highly selective D3 receptor antagonist, for the treatment of Schizophrenia and other CNS diseases. 
Racemic forms of formula I and their preparations have been disclosed in PCT publication WO 97/45403. The present invention has discovered that the (2S)-enantiomer of formula I is the form that possesses the superior desirable bioactivity. The present invention also provides a process for the synthesis, in a large scale, of said (2S)-enantiomer in a highly enantiomerically enriched form, which solved an extremely challenging problem of a long period of time.
PCT International Publication No. WO 97/45403 discloses aryl substituted cyclic amines as selective dopamine D3 ligands.
U.S. Pat. No. 5,708,018 discloses 2-aminoindans as selective dopamine D3 ligands.
The present invention provides compounds of formula I: 
or a pharmaceutically acceptable salt thereof wherein each R is independently C1-8 alkyl.
More preferably, a compound of formula I of the present invention is (2S)-(+)-2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention also provides:
a process for the preparation of (2S)-enantiomers of formulas I in a highly enantiomerically enriched form;
novel intermediates in a highly enantiomerically enriched form useful for preparing compounds of formula I;
a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (the composition preferably comprises a therapeutically effective amount of the compound or salt),
a method for treating a disease or condition in a mammal wherein a D3 receptor is implicated and modulation of a D3 receptor function is desired comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal;
a method for treating or preventing anxiety, obesity, depression, schizophrenia, a stress related disease (e.g. general anxiety disorder), panic disorder, sleep disorders, a phobia, mania, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the gastrointestinal or cardiovascular system, or sexual dysfunction in a mammal comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal;
a method for treating or preventing ADHD (attention deficit hyperactivity disorder), migraine, substance abuse (including smoking cessation), cognitive deficits, memory impairment, alzheimer""s disease, movement disorders including choreatic movements in huntington""s disease or motor complications such as dystonias and dyskinesias in Parkinson""s disease, extrapyramidal side effects related to the use of neuroleptics, and xe2x80x9cTicsxe2x80x9d including Tourette""s syndrome in a mammal comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal.
The following definitions are used, unless otherwise described.
The term alkyl refer to both straight and branched groups, but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-8 alkyl refers to alkyl of one to eight carbon atoms, inclusive.
Mammal refers to human or animals.
Pharmaceutically acceptable salts refer to organic acid addition salts such as tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, xcex1-ketoglutarate, xcex1-glycerophosphate, or suitable inorganic salts including hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate, and carbonate salts, etc.
The term xe2x80x9cchiral saltxe2x80x9d refers to a salt containing a chiral acid. The term xe2x80x9cchiral acidsxe2x80x9d refers to the acids having one or more chiral centers. Examples of chiral acids are tartaric acid, di-benzoyltartaric acid, di-para-toluoyltartaric acid, camphorsulfonic acid, and mandelic acid. The preferred chiral acid is mandelic acid.
All temperatures are in degrees Centigrade.
[xcex1]D25 refers to the angle of rotation of plane polarized light (specific optical rotation) at 25xc2x0 C. with the sodium D line (589 A).
The compounds of formula I are active orally or parenterally. Orally the formula I compounds can be given in solid dosage forms such as tablets or capsules, or can be given in liquid dosage forms such as elixirs, syrups or suspensions as is known to those skilled in the art. It is preferred that the formula I compounds be given in solid dosage form and that it be a tablet.
Typically, the compounds of formula I can be given in the amount of about 0.5 mg to about 250 mg/person, one to three times a day. Preferably, about 5 to about 50 mg/day in divided doses.
The exact dosage and frequency of administration depends on the particular compound of formula I used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the active compound in the patient""s blood and/or the patient""s response to the particular condition being treated.
Thus, the subject compounds, along with a pharmaceutically-acceptable carrier, diluent or buffer, can be administrated in a therapeutic or pharmacological amount effective to alleviate the central nervous system disorder with respect to the physiological condition diagnosed. The compounds can be administered intravenously, intramuscularly, topically, transdermally such as by skin patches, buccally or orally to man or other vertebrates.
The compositions of the present invention can be presented for administration to humans and other vertebrates in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions, oil in water and water in oil emulsions containing suitable quantities of the compound, suppositories and in fluid suspensions or solutions.
For oral administration, either solid or fluid unit dosage forms can be prepared. For preparing solid compositions such as tablets, the compound can be mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar pharmaceutical diluent or carrier materials. Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.
Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared. The forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup. Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
For parenteral administration, fluid unit dosage forms can be prepared utilizing the compound and a sterile vehicle. In preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. The composition can be frozen after filling into a vial and the water removed under vacuum. The lyophilized powder can then be sealed in the vial and reconstituted prior to use.
The present invention provides a process for preparing compounds of formula I in a highly enantiomerically enriched form as depicted in Scheme I. The starting material I-1 in Scheme I can be prepared according to the procedures described in Chart A of U.S. Pat. No. 5,708,018.
In step 1, compound I-1 is converted to compound I-2 as a racemic mixture via catalytic hydrogenation in the presence of an appropriate catalyst, such as palladium on carbon, W-2 Raney nickel or platinum on sulfide carbon, in an appropriate solvent, such as ethanol, THF, ethyl acetate or combinations thereof. The desired enantiomer I-2b can be obtained by treating structure I-2 with an appropriate chiral acid in an appropriate solvent to form the corresponding chiral salt complex, which subsequently crystallizes from the solvent. Resolutions to separate an individual enantiomer I-2a or I-2b from a racemic mixture often pose a significant challenge in the quest to obtain enantiomerically pure compound. In general, a wide variety of enantiomerically pure acids can provide some measure of enantiomer enrichment. However, the choice of the particular chiral acid and solvent system proves very important to the efficiency of the resolution (enantiomeric purity and chemical yield). The preferred chiral acids in the present invention for the resolution include tartaric acid, di-benzoyltartaric acid, di-para-toluoyltartaric acid, camphorsulfonic acid, and mandelic acid. The most preferred chiral acid is mandelic acid. An examination of resolving acids and solvent systems indicate that (R)-(xe2x88x92)-mandelic acid and (1R)-(xe2x88x92)-10-camphorsulfonic acid perform very well for the resolution of racemic I-2 to induce the crystallization of almost enantiomerically pure I-2b, with (R)-(xe2x88x92)mandelic acid being preferred. Note that it is not necessary to obtain enantiomer I-2b as 100% pure enantiomeric material at this stage of the synthesis since subsequent crystallization procedures in the following procedures will serve to provide a slight upgrade to the final enantiomeric purity. It will be apparent to those skilled in the art that other chiral acids commonly used to perform resolution of amines may also be useful for this resolution. Solvent systems in the present invention, which are found to be useful to optimize the recovery of compound I-2b, include alcohol solvents such as methanol, ethanol, isopropanol, etc. as well as co-solvents of alcohol(s), acetonitrile (ACN), or water in various proportions such as tetrahydrofuran (THF), ether, methyl tertiary butyl ether (MTBE), dimethoxyethane (DME), etc. The preferred solvent system in combination with (R)-(xe2x88x92)-mandelic acid is a mixture of methanol and tetrahydrofuran.
Next, alkylation of I-2b, in a form of free base or chiral salt complex, with an alkylation agent in the presence of an appropriate base and an appropriate polar solvent system at a temperature in a range of about 20xc2x0 C. to 90xc2x0 C. provides compound I-3. The appropriate base includes K2CO3, Na3PO4, Na2B4O7, etc. The preferred base is Na3PO4. The appropriate solvent includes ACN, dimethylformamide (DMF), or THF. The preferred solvent is ACN. The preferred temperature is in a range of from about 60xc2x0 C. to about 75xc2x0 C. Compound I-3 is then converted to compound I-4 by acetylation followed by hydrogenolysis in the presence of an appropriate catalyst, such as palladium on carbon or platinum on sulfide carbon, and an appropriate acetylation reagent such as acetic anhydride, or acetyl chloride with catalytic dimethylaminopyridine, in an appropriate solvent, such as acetic acid, an alcohol, water or combinations thereof, at a temperature in a range of from about 20xc2x0 C. to reflux. The preferred condition for this reaction is in acetic anhydride/acetic acid at a temperature in a range of from about 55xc2x0 C. to about 70xc2x0 C. Bromination of compound I-4 with a brominating reagent in the presence of an acid and a polar solvent system at a temperature in a range of from about xe2x88x9278xc2x0 C. to about room temperature provides compound I-5. The instant bromination provides an unexpected improvement in regioselectivity for bromination at the desired position by using an appropriate brominating reagent. A suitable brominating reagent may be Br2, dibromantin, N-bromosuccinimide (NBS), pyridinium tribromide (pyrHBr3). The preferred brominating reagent is pyridinium tribromide. The acid in the reaction is preferably a strong acid such as HBr, H2SO4, TiCl4, TFA, MeSO3H, Cl3CCO2H, Cl2CCO2H, or citric acid. The more preferred acid is TFA. The suitable polar solvent may be ACN, DMF, EtOAc, an alcohol such as methanol, CH2Cl2, MTBE, THF, etc. The preferred solvent is CH2Cl2. The preferred temperature is in a range from about xe2x88x9215xc2x0 C. to room temperature. Finally, carboxamidation I-5 in the presence of transition metal such as palladium, palladium on carbon or palladium acetate and associated ligands such as mono or bidentate phosphines in an appropriate solvent with an appropriate base at a temperature in a range from about 70xc2x0 C. to about 140xc2x0 C. provides the desired compound I-6. Preferred ligands include triphenylphosphine, tri-orthotolulyphosphine, or 1,3-bis(diphenylphosphino)propane. Preferred temperature is in a range from about 95xc2x0 C. to about 105xc2x0 C. The appropriate solvents include dimethylformamide, dioxane, toluene, dimethoxyethane, dimetylacetamide, etc. The preferred solvent is dimethylformamide. The appropriate base include potassium carbonate, tertiary amine bases, Na3PO4, LiHMDS, Li-amides, alkoxides, etc. The preferred base is potassium carbonate.
Without further elaboration, it is believe that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed example describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.